Alzheimer""s disease is a degenerative disorder of the human brain. Clinically, it appears as a progressive dementia. Its histopathology is characterized by degeneration of neurons, gliosis, and the abnormal deposition of proteins in the brain. Pathological hallmarks include neurofibrillary tangles (paired helical filaments) and amyloid deposits within the parenchyma and cerebral vasculature.
Recent studies indicate that a major component of the pathology of Alzheimer""s disease is chronic inflammation. See, J. Schnabel, Science, 260:1719-1720 (1993).
Administration of nonsteroidal anti-inflammatory drugs appears to slow the advance of Alzheimer""s disease. Understanding this inflammatory component of Alzheimer""s disease may lead to advances in methods of treating patients suffering from this disease.
The structure and physical properties of human non-pancreatic secretory phospholipase A2 (hereinafter called, xe2x80x9csPLA2xe2x80x9d) has been described in two articles, namely, xe2x80x9cCloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluidxe2x80x9d by Seilhamer, Jeffrey J.; Pruzanski, Waldemar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K.; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, 1989; pp. 5335-5338, and xe2x80x9cStructure and Properties of a Human Nonpancreatic Phospholipase A2xe2x80x9d by Kramer, Ruth M.; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry, Vol. 264, No. 10, Issue of Apr. 5, 1989; pp. 5768-5775, the disclosures of which are incorporated herein by reference.
It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids.
The scientific literature suggests NSAIDs may be beneficial in the treatment of Alzheimer""s Disease. Moreover, COX-2 inhibitors are currently being tested for treatment of Alzheimer""s.
PLA2 inhibitors have been proposed as treatment for Alzheimer""s disease (see, U.S. Pat. Nos. 5,478,857 and 5,563,164), but typically these have been cytosolic phospholipase A2 inhibitors.
Because of the debilitating effects of Alzheimer""s disease there continues to exist a need for effective treatments. This invention provides methods for the treatment of Alzheimer""s disease in mammals.
This invention is a method of treating a mammal, including a human, susceptible to having Alzheimer""s disease, to prevent or delay the onset of Alzheimer""s disease; said method comprising administering to said mammal a prophylactically effective amount of substituted tricyclic sPLA2 inhibitor or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.
This invention is also a method of treating a mammal, including a human, already afflicted with Alzheimer""s disease to prevent or diminish the rate of further deterioration; said method comprising administering to said mammal a therapeutically effective amount substituted tricyclic sPLA2 inhibitor compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof.
All temperatures stated herein are in degrees Celsius (xc2x0 C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.
The term xe2x80x9cprophylactically effective amountxe2x80x9d is the quantity of substituted tricyclic sPlA2 inhibitor required to prevent or significantly delay the onset of Alzheimer""s disease in a mammal susceptible (by reason of age, family history, etc.) to contracting Alzheimer""s disease.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d is the quantity of substituted tricyclic sPLA2 inhibitor sufficient to prevent or retard the progress of Alzheimer""s disease in a mammal already afflicted with Alzheimer""s disease.
The term xe2x80x9cparenteralxe2x80x9d means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, or intravenous.
The term xe2x80x9cactive compoundxe2x80x9d means one or more substituted tricyclic sPLA2 inhibitors used in the method of the invention as further described in Formula III or named below.
As used herein, the term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl tert butyl, n-pentyl, isopentyl, neopentyl, heptyl, hexyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and the like. The term xe2x80x9calkylxe2x80x9d includes xe2x80x94(C1-C2)alkyl, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C6)alkyl, xe2x80x94(C5-C14)alkyl, and xe2x80x94(C1-C10)alkyl.
The term xe2x80x9calkenylxe2x80x9d as used herein represents an olefinically unsaturated branched or linear group having at least one double bond. Examples of such groups include radicals such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl as well as dienes and trienes of straight and branched chains.
The term xe2x80x9calkynylxe2x80x9d denotes such radicals as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl as well as di- and tri-ynes.
The term xe2x80x9chaloxe2x80x9d means chloro, fluoro, bromo or iodo.
The term xe2x80x9cxe2x80x94(C1-C4)alkoxyxe2x80x9d, as used herein, denotes a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy and like groups, attached to the remainder of the molecule by the oxygen atom.
The term xe2x80x9cphenyl(C1-C4)alkylxe2x80x9d refers to a straight or branched chain alkyl group having from one to four carbon atoms attached to a phenyl ring which chain is attached to the remainder of the molecule. Typical phenylalkyl groups include benzyl, phenylethyl, phenylpropyl, phenylisopropyl, and phenylbutyl.
The term xe2x80x9cxe2x80x94(C1-C4)alkylthioxe2x80x9d defines a straight or branched alkyl chain having one to four carbon atoms attached to the remainder of the molecule by a sulfur atom. Typical xe2x80x94(C1-C4)alkylthio groups include methylthio, ethylthio, propylthio, butylthio and the like.
The term xe2x80x9cxe2x80x94(C3-C14)cycloalkylxe2x80x9d includes groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl and the like. The term xe2x80x9cxe2x80x94(C3-C14)cycloalkylxe2x80x9d includes and xe2x80x94(C3-C7)cycloalkyl.
The term, xe2x80x9cheterocyclic radicalxe2x80x9d, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pryidinyl, dipyridylyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
The term xe2x80x9ccarbocyclic radicalxe2x80x9d refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexeyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb), 
where n is an integer from 1 to 8.
The term, xe2x80x9cnon-interfering substituentxe2x80x9d, refers to radicals suitable for substitution at positions 1, 2, 3, 7 and/or 8 on the tricyclic nucleus (as depicted in Formula III) and radical(s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above. Illustrative non-interfering radicals are hydrogen, xe2x80x94(C1-C12)alkyl, xe2x80x94(C2-C6)alkenyl, xe2x80x94(C2-C6)alkynyl, xe2x80x94(C7-C12)aralkyl, xe2x80x94(C7-C12)alkaryl, xe2x80x94(C3-C8)cycloalkyl, xe2x80x94(C3-C8)cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, xe2x80x94(C1-C6)alkoxy, xe2x80x94(C2-C6)alkenyloxy, xe2x80x94(C2-C6)alkynyloxy, xe2x80x94(C1-C12)alkoxyalkyl, xe2x80x94(C1-C12)alkoxyalkyloxy, xe2x80x94(C1-C12)alkylcarbonyl, xe2x80x94(C1-Cl2)alkylcarbonylamino, xe2x80x94(C1-C12)alkoxyamino, xe2x80x94(C1-C12)alkoxyaminocarbonyl, xe2x80x94(C1-C12)alkylamino, xe2x80x94(C1-C6)alkylthio, xe2x80x94(C1-C12)alkylthiocarbonyl, xe2x80x94(C1-C6)alkylsulfinyl, xe2x80x94(C1-C6)alkylsulfonyl, xe2x80x94(C1-C6)haloalkoxy, xe2x80x94(C1-C6)haloalkylsulfonyl, xe2x80x94(C1-C6)haloalkyl, xe2x80x94(C1-C6)hydroxyalkyl, xe2x80x94(CH2)nCN, xe2x80x94(CH2)nNR9R10, xe2x80x94C(O)O(C1-C6 alkyl), xe2x80x94(CH2)nO(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, xe2x80x94(CONHSO2R), xe2x80x94CHO, amino, amidino, halo, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)nCO2H, cyano, cyanoguanidinyl, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, and (C1-C6)alkylcarbonyl; where n is from 1 to 8 and R9 and R10 are independently xe2x80x94(C1-C4)alkyl or phenyl(C1-C4)alkyl. A preferred group of non-interfering substituents include hydrogen, halo, xe2x80x94(C1-C3)alkyl, xe2x80x94(C3-C4)cycloalkyl, xe2x80x94(C3-C4)cycloalkenyl, xe2x80x94O(C1-C2)alkyl or xe2x80x94S(C1-C2)alkyl.
The term, xe2x80x9cacidic groupxe2x80x9d means an organic group which when attached to a tricyclic nucleus, through suitable linking atoms (hereinafter defined as the xe2x80x9cacid linkerxe2x80x9d), acts as a proton donor capable of hydrogen bonding. Illustrative of an acidic group are the following: 
where n is 1 to 8, R89 is a metal or xe2x80x94(C1-C10)alkyl, and R99 is hydrogen or xe2x80x94(C1-C10)alkyl.
The words, xe2x80x9cacid linkerxe2x80x9d refer to a divalent linking group symbolized as, xe2x80x94(La)xe2x80x94, which has the function of joining the 5 or 6 position of the tricyclic nucleus to an acidic group in the general relationship:
(tricyclic nucleus)-(La)-Acidic Group
The words, xe2x80x9cacid linker lengthxe2x80x9d, refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group xe2x80x94(La)xe2x80x94 that connects the 5 or 6 position of the tricyclic nucleus with the acidic group. The presence of a carbocyclic ring in xe2x80x94(La)xe2x80x94 counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of xe2x80x94(La)xe2x80x94. Illustrative acid linker groups are; 
where t is 1 to 5, Q is selected from the group xe2x80x94(CH2)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94Sxe2x80x94, and R84 and R85 are each independently selected from hydrogen, xe2x80x94(C1-C10)alkyl, aryl, xe2x80x94(C1-C10)alkaryl, xe2x80x94(C1-C10)aralkyl, carboxy, carbalkoxy, and halo, when t is one (1), groups (a), (b), (c) and (d) have acid linker lengths of 3, 3, 2, and 2, respectively.
The salts of the above tricyclics are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts include but are not limited to the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin.
Included within the definition of pharmaceutically acceptable salts are the relatively nontoxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)).
Compounds of the invention may have chiral centers and exist in optically active forms. R- and S-isomers and racemic mixtures are contemplated by this invention. A particular stereoisomer may be prepared by known methods using stereospecific reactions with starting materials containing asymmetric centers already resolved or, alternatively, by subsequent resolution of mixtures of stereoisomers using known methods.
Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives, such as, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic esters (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Other preferred prodrug esters include morpholinoethyloxy and diethylaminocarbonylmethoxy.
Carbazole and tetrahydrocarbazole SPLA2 inhibitors and methods of making these compounds are set out in U.S. patent application Ser. No. 09/063066 filed Apr. 21, 1998 (titled, xe2x80x9cSubstituted Carbazoles and 1,2,3,4-Tetrahydrocarbazolesxe2x80x9d), the entire disclosure of which is incorporated herein by reference. The method of the invention includes treatment of a mammal, including a human, with these compounds.
The method of the invention is for treatment of a mammal, including a human, afflicted with Alzheimer""s Disease, said method comprising administering to said human a therapeutically effective amount carbazole or tetrahydrocarbazole represented by the following:
A compound of the formula (Ie) 
wherein;
A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position;
one of B or D is nitrogen and the other is carbon;
Z is cyclohexenyl, phenyl, pyridyl, wherein the nitrogen is at the 1-, 2-, or 3-position, or a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position, and nitrogen at the 1-, 2-, 3- or 4-position;
 is a double or single bond;
R20 is selected from groups (a), (b) and (c) where;
(a) is xe2x80x94(C5-C20)alkyl, xe2x80x94(C5-C20)alkenyl, (C5-C20)alkynyl, carbocyclic radicals, or heterocyclic radicals, or
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or
(c) is the group xe2x80x94(L)xe2x80x94R80; where, xe2x80x94(L)xe2x80x94 is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur; wherein the combination of atoms in xe2x80x94(L)xe2x80x94 are selected from the group consisting of (i) carbon and hydrogen only, (ii) one sulfur only, (iii) one oxygen only, (iv) one or two nitrogen and hydrogen only, (v) carbon, hydrogen, and one sulfur only, and (vi) and carbon, hydrogen, and oxygen only; and where R80 is a group selected from (a) or (b);
R21 is a non-interfering substituent;
R1xe2x80x2 is xe2x80x94NHNH2, xe2x80x94NH2 or xe2x80x94CONH2;
R2xe2x80x2 is selected from the group consisting of xe2x80x94OH, and xe2x80x94O(CH2)tR5xe2x80x2 where
R5xe2x80x2 is H, xe2x80x94CN, xe2x80x94NH2, xe2x80x94CONH2, xe2x80x94CONR9R10xe2x80x94NHSO2R15; xe2x80x94CONHSO2R15, where R15 is xe2x80x94(C1-C6)alkyl or xe2x80x94CF3; phenyl or phenyl substituted with xe2x80x94CO2H or xe2x80x94CO2(C1-C4)alkyl; and xe2x80x94(La)-(acidic group), wherein xe2x80x94(La)xe2x80x94 is an acid linker having an acid linker length of 1 to 7 and t is 1-5;
R3xe2x80x2 is selected from non-interfering substituent, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals, and heterocyclic radicals substituted with non-interfering substituents; or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof;
provided that; when R3xe2x80x2 is H, R20 is benzyl and m is 1 or 2; R2xe2x80x2 cannot be xe2x80x94O(CH2)mH; and
provided that when D is nitrogen, the heteroatom of Z is selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the 1-, 2-, 3- or 4-position.
Preferred in the practice of the method of the invention are compounds represented by the formula (IIe): 
wherein;
Z is cyclohexenyl, or phenyl;
R21 is a non-interfering substituent;
R1 is xe2x80x94NHNH2 or xe2x80x94NH2;
R2 is selected from the group consisting of xe2x80x94OH and xe2x80x94O(CH2)mR5 where
R5 is H, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CO2(C1-C4 alkyl); 
xe2x80x83where R6 and R7 are each independently xe2x80x94OH or xe2x80x94O(C1-C4)alkyl; xe2x80x94SO3H, xe2x80x94SO3(C1-C4 alkyl), tetrazolyl, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NHSO2R15; xe2x80x94CONHSO2R15, where R15 is xe2x80x94(C1-C6)alkyl or xe2x80x94CF3, phenyl or phenyl substituted with xe2x80x94CO2H or xe2x80x94CO2(C1-C4)alkyl where m is 1-3;
R3 is H, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6)alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl; or xe2x80x94(CH2)nR8 where R8 is H, xe2x80x94CONH2, xe2x80x94NR9R10, xe2x80x94CN or phenyl where R9 and R10 are independently xe2x80x94(C1-C4)alkyl or -phenyl(C1-C4)alkyl and n is 1 to 8;
R4 is H, xe2x80x94(C5-C14)alkyl, xe2x80x94(C3-C14)cycloalkyl, pyridyl, phenyl or phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94(C1-C4)alkoxy, xe2x80x94CN, xe2x80x94(C1-C4)alkylthio, phenyl(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl, phenyl, phenoxy or naphthyl;
or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt, thereof.
Preferred specific compounds including all salts and prodrug derivatives thereof, for practicing the method of the invention are as follows:
9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid hydrazide;
9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;
[9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid sodium salt;
[9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid;
methyl[9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl]oxyacetic acid;
9-benzyl-7-methoxy-5-cyanomethyloxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;
9-benzyl-7-methoxy-5-(1H-tetrazol-5-yl-methyl)oxy)-1,2,3,4-tetrahydrocarbazole-4-carboxamide;
{9-[(phenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-yl}oxyacetic acid;
{9-[(3-fluorophenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4-yl}oxyacetic acid;
{9-[(3-methylphenyl)methyl]-5-carbamoyl-2-methylcarbazol-4-yl}oxyacetic acid;
{9-[(phenyl)methyl]-5-carbamoyl-2-(4-trifluoromethylphenyl)-carbazol-4-yl}oxyacetic acid;
9-benzyl-5-(2-methanesulfonamido)ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;
9-benzyl-4-(2-methanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide;
9-benzyl-4-(2-trifluoromethanesulfonamido)ethyloxy-2-methoxycarbazole-5-carboxamide;
9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide;
9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-5-carboxamide;
[5-carbamoyl-2-pentyl-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-2-(1-methylethyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-9-(phenylmethyl)-2-[(tri(-1-methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-2-phenyl-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-2-(4-chlorophenyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-9-(phenylmethyl)-2-[(tri(-1-methylethyl)silyl)oxymethyl]carbazol-4-yl]oxyacetic acid, lithium salt;
{9-[(phenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3,5-dimethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-iodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-Chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2,3-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2,6-difluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-trifluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
the {9-[(2-Biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
[9-Benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbaole-5-yl]oxyacetic acid;
{9-[(2-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
{9-[(3-Pyridyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid;
[9-benzyl-4-carbamoyl-8-methyl-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid;
[9-benzyl-5-carbamoyl-1-methylcarbazol-4-yl]oxyacetic acid;
[9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid;
[9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl]oxyacetic acid;
[9-benzyl-4-carbamoyl-8-chloro-1,2,3,4-tetrahydrocarbazol-5-yl]oxyacetic acid;
[9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl]oxyacetic acid;
[9-[(Cyclohexyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid;
[9-[(Cyclopentyl)methyl]-5-carbamoylcarbazol-4-yl]oxyacetic acid;
5-carbamoyl-9-(phenylmethyl)-2-[[(propen-3-yl)oxy]methyl]carbazol-4-yl]oxyacetic acid;
[5-carbamoyl-9-(phenylmethyl)-2[(propyloxy)methyl]carbazol-4-yl]oxyacetic acid; 9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)-1,2,3,4-tetrahydrocarbazole-4-carboxamide;
9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-carboxamide;
9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl)oxy)carbazole-4-carboxamide;
9-benzyl-7-methoxy-5-((carboxamidomethyl)oxy)carbazole-4-carboxamide; and
[9-Benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbaole-5-yl]oxyacetic acid
or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt, thereof.
Other desirable carbazole compounds suitable for practicing the method of the invention are selected from those represented by the formula (XXX): 
wherein:
R1 is xe2x80x94NHNH2, or xe2x80x94NH2;
R2 is selected from the group consisting of xe2x80x94OH and xe2x80x94O(CH2)mR5 where
R5 is H, xe2x80x94CO2H, xe2x80x94CO2(C1-C4 alkyl); 
xe2x80x83where R6 and R7 are each independently xe2x80x94OH or xe2x80x94O(C1-C4)alkyl; xe2x80x94SO3H, xe2x80x94SO3(C1-C4 alkyl), tetrazolyl, xe2x80x94CN, xe2x80x94NH2, xe2x80x94NHSO2R15; xe2x80x94CONHSO2R15, where R15 is xe2x80x94(C1-C6)alkyl or xe2x80x94CF3, phenyl or phenyl substituted with xe2x80x94CO2H or xe2x80x94CO2(C1-C4)alkyl where m is 1-3;
R3 is H, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6)alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl; or xe2x80x94(CH2)nR8 where R8 is H, xe2x80x94CONH2, xe2x80x94NR9R10, xe2x80x94CN or phenyl where R9 and R10 are independently xe2x80x94(C1-C4)alkyl or -phenyl(C1-C4)alkyl and n is 1 to 8;
R4 is H, xe2x80x94(C5-C14)alkyl, xe2x80x94(C3-C14)cycloalkyl, pyridyl, phenyl or phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, xe2x80x94CF3, xe2x80x94OCF3, xe2x80x94(C1-C4)alkoxy, xe2x80x94CN, xe2x80x94(C1-C4)alkylthio, phenyl(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl, phenyl, phenoxy or naphthyl;
A is phenyl or pyridyl wherein the nitrogen is at the 5-, 6-, 7- or 8-position;
Z is cyclohexenyl, phenyl, pyridyl wherein the nitrogen is at the 1-, 2- or 3-position or a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur or oxygen at the 1-, 2- or 3-position and nitrogen at the 1-, 2-, 3- or 4-position, or
wherein one carbon on the heterocyclic ring is optionally substituted with xe2x95x90O;
or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof;
provided that one of A or Z is a heterocyclic ring.
Further desirable specific compounds suitable for the method of the invention are selected from the following: (R,S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl)oxyacetic acid; (R,S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia-1,2,3,4-tetrahydrocarbazol-5-yl)oxyacetic acid; [N-benzyl-1-carbamoyl-1-aza-1,2,3,4-tetrahydrocarbazol-8-yl]oxyacetic acid; 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6,7,8,9-tetrahydropyrido[1,2-a]indole; (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano[3,4-b]indol-5-yl)oxyacetic acid; 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano[3,4-b]indole; 2-[(2,9 bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-beta-carbolin-5-yl)oxy]acetic acid or a pharmaceutically acceptable racemate, solvate, tautomer, optical isomer, prodrug derivative or salt thereof.
Particularly preferred compounds for the treatment of Alzheimer""s Disease are represented by the formulae (Xe) and (XIe) below: 
For all of the above compounds of the carbazole or tetrahydrocarbazole type it is advantageous to use them in their (i) acid form, or (ii) pharmaceutically acceptable (e.g., Na, K) form, or (iii) and prodrugs derivatives (e.g., methyl ester, ethyl ester, n-butyl ester, morpholino ethyl ester).
Prodrugs are derivatives of sPLA2 inhibitors used in the method of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specific preferred prodrugs are ester prodrugs inclusive of methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, sec-butyl, tert-butyl ester, N,N-diethylglycolamido ester, and morpholino-N-ethyl ester. Methods of making ester prodrugs are disclosed in U.S. Pat. No. 5,654,326. Additional methods of prodrug synthesis are disclosed in U.S. Provisional Patent Application Serial No. 60/063280 filed Oct. 27, 1997 (titled, N,N-diethylglycolamido ester Prodrugs of Indole sPLA2 Inhibitors), the entire disclosure of which is incorporated herein by reference; U.S. Provisional Patent Application Serial No. 60/063646 filed Oct. 27, 1997 (titled, Morpholino-N-ethyl Ester Prodrugs of Indole sPLA2 Inhibitors), the entire disclosure of which is incorporated herein by reference; and U.S. Provisional Patent Application Serial No. 60/063284 filed Oct. 27, 1997 (titled, Isopropyl Ester Prodrugs of Indole sPLA2 Inhibitors), the entire disclosure of which is incorporated herein by reference.
Carbazole and tetrahydrocarbazole sPLA2 inhibitor compounds useful for practicing the method of the invention may be made by the following general methods:
The compounds of formula Ie where Z is cyclohexene are prepared according to the following reaction Schemes Ig(a) and (c). 
wherein;
R1 is xe2x80x94NH2, R3(a) is H, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo, or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6)alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl, xe2x80x94(C1-C6)alkoxy(C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy(C1-C6)alkenyl; or xe2x80x94(CH2)nR8 where R8 is H, xe2x80x94CONH2, xe2x80x94NR9R10, xe2x80x94CN or phenyl where R9 and R10 are independently hydrogen, xe2x80x94CF3, phenyl, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl or -phenyl(C1-C4)alkyl and n is 1 to 8;
when R1 is xe2x80x94NHNH2, R3(a) is H, xe2x80x94O(C1-C4)alkyl, halo, xe2x80x94(C1-C6)alkyl, phenyl, xe2x80x94(C1-C4)alkylphenyl; phenyl substituted with xe2x80x94(C1-C6)alkyl, halo or xe2x80x94CF3; xe2x80x94CH2OSi(C1-C6)alkyl, furyl, thiophenyl, xe2x80x94(C1-C6)hydroxyalkyl, xe2x80x94(C1-C6)alkoxy(C1-C6)alkyl, xe2x80x94(C1-C6)alkoxy(C1-C6)alkenyl; or xe2x80x94(CH2)nR8 where R8 is H, xe2x80x94NR9R10, xe2x80x94CN or phenyl where R9 and R10 are independently hydrogen, xe2x80x94CF3, phenyl, xe2x80x94(C1-C4)alkyl, xe2x80x94(C1-C4)alkylphenyl or -phenyl(C1-C4)alkyl and n is 1 to 8;
R2(a) is xe2x80x94OCH3 or xe2x80x94OH.
An appropriately substituted nitrobenzene (1) can be reduced to the aniline (2) by treatment with a reducing agent, such as hydrogen in the presence of Pd/C, preferably at room temperature.
Compound (2) is N-alkylated at temperatures of from about 0 to 20xc2x0 C. using an alkylating agent such as an appropriately substituted aldehyde and sodium cyanoborohydride to form (3). Alternately, an appropriately substituted benzyl halide may be used for the first alkylation step. The resulting intermediate is further N-alkylated by treatment with 2-carbethoxy-6-bromocyclohexanone, preferably at temperatures of about 80xc2x0 C. to yield (4) or by treatment with potassium hexamethyldisilazide and the bromoketoester.
The product (4) is cyclized to the tetrahydrocarbazole (5) by refluxing with ZnCl2 in benzene for from about 1 to 2 days, preferably at 80xc2x0 C. (Ref 1). Compound (5) is converted to the hydrazide (6) by treatment with hydrazine at temperatures of about 100xc2x0 C., or to the amide (7) by reacting with methylchloroaluminum amide in benzene. (Ref 2) Alternatively, (7) may be produced by treatment of (6) with Raney nickel active catalyst.
It will be readily appreciated that when R3(a) is: 
conversion to the amide will also be achieved in this procedure.
Compounds (6) and (7) may be dealkylated, preferably at 0xc2x0 C. to room temperature, with a dealkylating agent, such as boron tribromide or sodium thioethoxide, to give compound (7) where R2(a) is xe2x80x94OH, which may then be further converted to compound (9), by realkylating with a base, such as sodium hydride, and an alkylating agent, such as Br(CH2)mR5, where R5 is the carboxylate or phosphonic diester or nitrile as defined above. Conversion of R2 to the carboxylic acid may be accomplished by treatment with an aqueous base. When R2 is nitrile, conversion to the tetrazole may be achieved by reacting with tri-butyl tin azide or conversion to the carboxamide may be achieved by reacting with basic hydrogen peroxide. When R2 is the phosphonic diester, conversion to the acid may be achieved by reacting with a dealkylating agent such as trimethylsilyl bromide. The monoester may be accomplished by reacting the diester with an aqueous base.
When R2 and R3 are both methoxy, selective demethylation can be achieved by treating with sodium ethanethiolate in dimethylformamide at 100xc2x0 C. Ref 1 Julia, M.; Lenzi, J. Preparation d""acides tetrahydro-1,2,3,4-carbazole-1 ou-4. Bull. Soc. Chim. France, 1962, 2262-2263. Ref 2 Levin, J. I.; Turos, E.; Weinreb, S. M. An alternative procedure for the aluminum-mediated conversion of esters to amides. Syn. Comm., 1982, 12, 989-993.
An alternative synthesis of intermediate (5) is shown in Scheme I(b), as follows. 
where PG is a protecting group;
R3a is as defined in Scheme 1, above.
The aniline (2) is N-alkylated with 2-carbethoxy-6-bromocyclohexanone in dimethyl formamide in the presence of sodium bicarbonate for 8-24 hours at 50xc2x0 C. Preferred protecting groups include methyl, carbonate, and silyl groups, such as t-butyldimethylsilyl. The reaction product (4xe2x80x2) is cyclized to (5xe2x80x2) using the ZnCl2 in benzene conditions described in Scheme I(a), above. N-alkylation of (5xe2x80x2) to yield (5) is accomplished by treatment with sodium hydride and the appropriate alkyl halide in dimethylformamide at room temperature for 4-8 hours. 
As discussed in Scheme I above, carbazole (5) is hydrolyzed to the carboxylic acid (10) by treatment with an aqueous base, preferably at room temperature to about 100xc2x0 C. The intermediate is then converted to an acid chloride utilizing, for example, oxalyl chloride and dimethylformamide, and then further reacted with a lithium salt of (S) or (R)-4-alkyl-2-oxazolidine at a temperature of about xe2x88x9275xc2x0 C., to give (11a) and (11b), which are separable by chromatography.
The diastereomers are converted to the corresponding enantiomeric benzyl esters (12) by brief treatment at temperatures of about 0xc2x0 C. to room temperature with lithium benzyl oxide. (Ref 3) The esters (12) are then converted to (7) preferably by treatment with methylchloroaluminum amide (Ref 2, above) or, alternately, by hydrogenation using, for example, hydrogen and palladium on carbon, as described above, to make the acid and then reacting with an acyl azide, such as diphenylphosphoryl azide followed by treatment with ammonia. Using the procedure described above in Scheme I, compound (9a) or (9b) may be accomplished. Ref 3 Evans, D. A.; Ennis, M. D.; Mathre, D. J. Asymmetric alkylation reactions of chiral imide enolates. A practical approach to the enantioselective synthesis of alphasubstituted carboxylic acid derivatives. J. Am. Chem. Soc., 1982, 104, 1737-1738.
Compounds of formula Ie where Z is phenyl can be prepared as follows in Schemes III(a)-(f), below. 
A 1,2,3,4-tetrahydrocarbazole-4-carboxamide or 4-carboxhydrazide (13) is dehydrogenated by refluxing in a solvent such as carbitol in the presence of Pd/C to produce the carbazole-4-carboxamide. Alternately, treatment of (13) with DDQ in an appropriate solvent such as dioxane yields carbozole (14).
Depending on the substituent pattern oxidation as described above may result in de-alkylation of the nitrogen. For example when R3 is substituted at the 8-position with methyl, oxidation results in dealkylation of the nitrogen which may be realkylated by treatment with sodium hydride and the appropriate alkyl halide as described in Scheme I(a) above to prepare the deired product (14). 
Benzoic acid derivative (16) where X is preferably chlorine, bromine or iodine and the protecting group is preferably xe2x80x94CH3, are reduced to the corresponding aniline (25) with a reducing agent, such as stannous chloride in the presence of acid under the general conditions of Sakamoto et al, Chem Pharm. Bull. 35 (5), 1823-1828 (1987).
Alternatively, reduction with sodium dithionite in the presence of a base, such as sodium carbonate in a noninterferring solvent, such as water, ethanol, and/or tetrahydrofuran affords starting material (16).
Alternatively, reduction by hydrogenation over a sulfided platinum catalyst supported on carbon with hydrogen at 1 to 60 atmospheres in a noninterfering solvent, preferably ethyl acetate, to form a starting material (16).
The reactions are conducted at temperatures from about 0 to 100xc2x0 C. preferably at ambient temperature, and are substantially complete in about 1 to 48 hours depending on conditions.
The aniline (25) and dione (15) are condensed under dehydrating conditions, for example, using the general procedure of Iida, et al., (Ref 5), with or without a noninterfering solvent, such as toluene, benzene, or methylene chloride, under dehydrating conditions at a temperature about 10 to 150xc2x0 C. The water formed in the process can be removed by distillation, azetropic removal via a Dean-Stark apparatus, or the addition of a drying agent, such as molecular sieves, magnesium sulfate, calcium carbonate, sodium sulfate, and the like.
The process can be performed with or without a catalytic amount of an acid, such a p-toluenesulfonic acid or methanesulfonic acid. Other examples of suitable catalysts include hydrochloric acid, phenylsulfonic acid, calcium chloride, and acetic acid.
Examples of other suitable solvents include tetrahydrofuran, ethyl acetate, methanol, ethanol, 1,1,2,2-tetrachloroethane, chlorobenzene, bromobenzene, xylenes, and carbotetrachloride.
The condensation of the instant process is preferably carried out neat, at a temperature about 100 to 150xc2x0 C. with the resultant water removed by distillation via a stream of inert gas, such as, nitrogen or argon.
The reaction is substantially complete in about 30 minutes to 24 hours.
Intermediate (26) may then be readily cyclized in the presence of a palladium catalyst, such as Pd(OAc)2 or Pd(PPh3)4 and the like, a phosphine, preferably a trialkyl- or triarylphosphine, such as triphenylphosphine, tri-o-tolylphosphine, or tricyclohexylphosphine, and the like, a base, such as, sodium bicarbonate, triethylamine, or diisopropylethylamine, in a noninterfering solvent, such as, acetonitrile, triethylamine, or toluene at a temperature about 25 to 200xc2x0 C. to form (19).